Cartilage is considerably elastic that plays a role in the construction of skeleton together with bone and the protection of internal organs. Cartilage tissue consists of chondrocytes and cartilage matrix surrounding the same.
Cartilage is formed by mesenchyme-originated chondroblasts which cells produce matrix in circumference in the process of cell division and growth. The cartilage matrix consists of amorphous matrix and fibrous components, and is classified into the following groups according to the ratio of components: (1) hyaline cartilage (articular cartilage, costicartilage, thyroid cartilage etc.);(2) fibrocartilage (discus intervertebrali, pubic symphysis etc.); and (3) elastic cartilage (pharynx lid cartilage, cartilage of acoustic meatus, auricular cartilage, etc.) IGAKU-DAIJITEN, 18th edition, published by Nanzando, pp. 1542.
The main components of cartilage matrix are proteoglycan and collagen (Type II, Type IX and the like). It is known that proteoglycan participates in the imbibition (swelling) nature peculiar to cartilage tissue, and collagen in the rigidity of cartilage against the tension and shearing force.
In proteoglycan of cartilage matrix, it is considered that glucosaminoglycans such as chondroitin sulfate, keratan sulfate are connected with a core protein of about 220,000 molecular weight to form macromolecules, wherein glucosaminoglycans hydrates many water molecules, which contributes to the imbibition nature of cartilage. The Bone, Vol. 4, pp. 8 (1994).
Articular cartilage has a calcification layer at the transmigration region with bone tissue, and, after the completion of growth, nutrients are supplied to chondrocytes from synovial fluid and are hardly supplied directly from blood. In addition, articular cartilage is formed from hyaline cartilage of high cell differentiation degree, and hence is a sensitive organ with extremely low regenerative ability.
The surface of articular cartilage is covered by highly viscous synovial fluid, and by virtue of lubrication mechanism of lubricant comprising as a principal component hyaluronic acid-protein complex, the smooth joint kinematics is maintained. However, it is considered that there is so-called durability in, articular cartilage, and alteration of joints with aging is unavoidable physiological phenomenon.
Examples of known diseases caused by cartilage disorder include osteoarthrosis, chondrodystrophy, degenerative discopathy or meniscus injury.
Among them, osteoarthrosis is a disease wherein a proliferative change of bone and articular cartilage occurs on the basis of a regressive change of tissue constituting a joint, mainly, articular cartilage, finally leading to a remarkable morphological change of the joint, which disease has markedly increased with the aging of population. In particular, the knee joint anthropathy can prevent patients from maintaining the standing position or walking normally as the pathology progresses, and lead to the significant decrease of their ADL (Ability of Daily Life) which possibly results in a bedridden condition.
Treatment of osteoarthrosis can be classified mainly into conservative treatment and surgical therapy. Conservative treatment is carried out by the following methods, for example, (1) administration of non-steroidal antiinflammatory analgesic; (2) thermotherapy; (3) control of weight; (4) therapy with braces; (5) intra-articular infusion of steroidal antiinflammatory analgesic; (6) intra-articular infusion of hyaluronate formulation. In cases wherein conservative treatment is ineffective, or the disease is in progressed or terminal stage, surgical therapy is conducted by (a) arthroscopic irrigation surgery; (b) high tibial osteotomy or (c) artificial joint replacement, and the like. Senility and Disorder, Vol. 10, 2nd. issue, pp. 61-69, (1997) & 6th issue, pp. 66-77 (1997).
There are various compounds having PDE4 inhibitory activity, which can suppress the release of inflammatory mediator by inhibiting the PDE4 activity. J. Mol. Cell. Cardiol., 12 (Suppl.II), S61 (1989).
It is described that a compound having PDE4 inhibitory activity suppresses the production of TNF-α which is a cytokine released from mononuclear phagocytes in response to immunostimulants, and is useful in treatment of various inflammatory diseases caused by TNF-α. JP 2000-503678A, JP 2000-502724A, JP 2000-510105A, JP 2000-514804A, 2000-502350A, JP 2000-501741A, and the like.
However, it has not been known that PDE4 inhibitor is effective for reparative treatment of cartilage diseases at all.